The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy.
Por:
Gavazzi F, Charsar B, Hamilton E, Erler JA, Patel V, Woidill S, Sevagamoorthy A, Helman G, Schmidt J, Pizzino A, Muirhead K, Takanohashi A, Bonkowsky JL, Meyerhoffer K, Simons C, Doi H, Satoko M, Matsumoto N, Delgado MR, Sanchez-Castillo M, Wang J, de Carvalho DR, Tournev I, Chamova T, Jordanova A, Clegg NJ, Nicita F, Bertini E, Teng M, Williams D, Tonduti D, Houlden H, Stellingwerff M, Wassmer E, Garcia-Cazorla A, Bernard G, Mirchi A, Toutounchi H, Wolf NI, van der Knaap MS, Shults J, Adang LA and Vanderver AL
Publicada:
1 mar 2025
Ahead of Print:
1 feb 2025
Resumen:
We establish the natural history of pediatric-onset TUBB4A-related leukodystrophy to improve clinical trial readiness through a medical record-based longitudinal study. An international cohort of 216 individuals with pediatric-onset TUBB4A-related leukodystrophy was included. Demographic information and medical events were extracted from medical records or publications. Retrospective scores (Gross Motor Function - Metachromatic Leukodystrophy [GMFC-MLD] and Communication Function Classification System [CFCS]) were applied to assess function. Survival analysis distinguished differences in longitudinal neurocognitive function and time to event outcomes between subtypes. A decision tree predicted independent ambulation from early motor milestones. Genotype (p.Asp249Asn vs non-p.Asp249Asn) and independent sitting by age 9 months predicted ambulation by 3 years, and stratification into three subgroups: early-infantile (non- sitting by 9 months), late-infantile (normal early milestones without the common p.Asp249Asn mutation), and a cohort of p.Asp249Asn late-infantile onset individuals. Median age at symptom onset was 0.71 years (interquartile range: [0.33, 1.50]). Common symptoms at onset include delayed development and tone abnormalities (n = 125, 66.5 % and n = 77, 43.0 %). The most common medical complications included scoliosis (N = 51/142), hip dislocation (N = 30/101), and seizures (N = 51/163). The early-infantile more severely affected cohort had a greater prevalence of G-tube placement, scoliosis, and seizure compared to the late-infantile form (p < 0.01). Peak motor and communication abilities were comparable between the p.Asp249Asn and the late infantile cohorts. Despite the acquisition of early milestones, individuals with p.Asp249Asn showed a more rapid decline of functional abilities compared to other late infantile forms (log-rank p = 0.0002). Better understanding of TUBB4A-related leukodystrophy subtypes will improve clinical care, allow targeted preventive interventions, and permit disease stratification for future disease-modifying clinical trials.
Filiaciones:
Gavazzi F:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Charsar B:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Hamilton E:
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Netherlands
Erler JA:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Patel V:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Woidill S:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Sevagamoorthy A:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Helman G:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Schmidt J:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Pizzino A:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Muirhead K:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Takanohashi A:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Bonkowsky JL:
Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
Center for Personalized Medicine, Primary Children's Hospital, Salt Lake City, UT, USA
Meyerhoffer K:
Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
Simons C:
Murdoch Childrens Research Institute, Melbourne, Australia
Doi H:
Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Satoko M:
Department of Human Genetics, Yokoama City University, Yokohama, Japan
Matsumoto N:
Department of Human Genetics, Yokoama City University, Yokohama, Japan
Delgado MR:
Department of Neurology, University of Texas Southwestern Medical Center, USA
Sanchez-Castillo M:
TGen's Center for Rare Childhood Disorders, Phoenix, AZ, USA
Wang J:
Department of Pediatrics, Peking University First Hospital, Beijing, China
de Carvalho DR:
Genetic Unit, SARAH Rehabilitation Hospital, Brasilia, Brazil
Tournev I:
Clinic of Nervous Diseases, University Hospital Aleksandrovska, Department of Neurology, Medical University-Sofia, Bulgaria
Department of Cognitive Science and Psychology, New Bulgarian University, Bulgaria
Chamova T:
Department of Neurology, University Hospital Alexandrovska, Medical University Sofia, Sofia, Bulgaria
Jordanova A:
Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University - Sofia, Sofia, Bulgaria
Molecular Neurogenomics Group, Center for Molecular Neurology, VIB, Antwerpen, Belgium
Molecular Neurogenomics Group, Center for Molecular Neurology, Department of Biomedical Sciences, University of Antwerp, Antwerpen, Belgium
Clegg NJ:
Division of Clinical Research, Department of Research, Scottish Rite for Children, Dallas, TX, USA
Nicita F:
Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
Bertini E:
Research Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy
Teng M:
Synaptixbio Ltd, Fermi Avenue, Harwell, UK
Williams D:
Synaptixbio Ltd, Fermi Avenue, Harwell, UK
Tonduti D:
Unit of Pediatric Neurology, C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Milan, Italy
Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy
Houlden H:
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK
Stellingwerff M:
Department of Pediatric Surgery, Vrije Universiteit, Amsterdam, Netherlands
Wassmer E:
Neurology Department, Birmingham Children's Hospital, Institute of Health and Neurodevelopment, Aston University, Birmingham, UK
Garcia-Cazorla A:
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Neurology Department, Neurometabolic Unit and Synaptic Metabolism Lab, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, metabERN and CIBERER-ISCIII, Barcelona, Spain
Bernard G:
Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada
Mirchi A:
Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada
Toutounchi H:
Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada
Wolf NI:
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Vrije Universiteit, Amsterdam, Netherlands
van der Knaap MS:
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Vrije Universiteit, Amsterdam, Netherlands
Shults J:
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Adang LA:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Vanderver AL:
Neurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Green Submitted, Green Published
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